An increasing body of evidence suggests that the parathyroid cell recognizes changes in calcium (Ca++) concentration via a cell surface receptor like mechanism. The putative divalent cation "receptor(s)" may be linked to several intracellular effector systems through one or more guanine nucleotide regulatory (G) proteins. Thus, this signal recognition/transduction system may be analogous to the G-protein-coupled, cell surface receptors through which a variety of more classical hormones and neurotransmitters regulate cellular function (e.g. beta adrenergic receptors). There are as yet, however, very limited data on the pharmacology of the regulation of parathyroid function by divalent cations. The overall goal of this proposal is to provide further support for the concept of a Ca++ receptor by determining whether the putative, parathyroid Ca++ receptors shares certain pharmacological properties of other cell surface receptors coupled to G-proteins, by addressing the following specific aims: (1) Specific Aim 1 will be to compare the relative potencies of various di- and trivalent cations as receptor "agonists" in regulating cAMP content, PI turnover cytosolic Ca++, and PTH release and to determine the feasibility of quantifying 45Ca binding to the Ca++ receptor. (2) Specific Aim 2 will be to determine whether chronic exposure to divalent cations modulates Ca++-mediated responses (homologous regulation) or whether exposure to agents acting through other cell surface receptors (i.e. beta-receptor or PGF2 alpha receptors) also modifies the effects of Ca++ on parathyroid function (heterologous regulation). (3) Specific Aim 3 will be to quantify the degree of apparent cooperativity in the effects of extracellular calcium on parathyroid function by calculating Hill coefficients for the inhibition of cAMP and PTH release and increases in cytosolic Ca++ and PI turnover produced by divalent cations. (4) Specific Aim 4 will be to determine whether the effects of the lectin concanavalin A on parathyroid function can be explained by binding to the cell surface at or near the putative divalent cation receptor. These studies may provide further insight into the mechanisms by which extracellular calcium and other factors regulate parathyroid hormone secretion from normal as well as pathologic parathyroid tissue.